The present invention relates generally to particulate drug delivery compositions comprising water-insoluble active agents and their methods of production. The invention is particularly suited for producing particles for pharmaceutical applications.
The need for effective therapeutic treatment of patients has resulted in the development of a variety of pharmaceutical formulation delivery techniques. One traditional technique involves the oral delivery of a pharmaceutical formulation in the form of a pill, capsule, elixir, or the like. However, oral delivery can in some cases be undesirable. For example, many pharmaceutical formulations may be degraded in the digestive tract before they can be effectively absorbed by the body. Inhaleable drug delivery, where an aerosolized pharmaceutical formulation is orally or nasally inhaled by a patient to deliver the formulation to the patient's respiratory tract, has proven to be a particularly effective and/or desirable alternative. For example, in one inhalation technique, an aerosolized pharmaceutical formulation provides local therapeutic treatment or prophylaxis to a portion of the respiratory tract, such as the lungs, to treat diseases of the lung such as asthma, emphysema, and cystic fibrosis. In another inhalation technique, a pharmaceutical formulation is delivered deep within a patient's lungs where it may be absorbed into the blood stream for systemic treatment or prophylaxis of a disease.
Many types of aerosolization devices exist including devices that aerosolize a dry powder pharmaceutical formulation, devices comprising a liquid or powder pharmaceutical formulation stored in or with a propellant, devices which use a compressed gas to aerosolize a liquid or suspension pharmaceutical formulation, and similar devices. However, the formulation of stable and reproducibly aerosolizable water-insoluble active agents has proven to be a difficult task. For example, liquid formulations comprising insoluble active agents may not be delivered in sufficiently high concentrations for easy dosing of a therapeutic agent. Previous attempts at producing pharmaceutical formulations comprising insoluble drugs include size reduction of drug crystals by micronization, milling, high pressure homogenization, and ultrasound or the development of drug delivery vehicles to solubilize or complex the poorly soluble drug, such as by using emulsions, microemulsions, solid lipid nanoparticles, and cyclodextrins. However, these solutions are often prohibitively costly and often produce poor results.
One technique for forming a pharmaceutical formulation comprising an insoluble active agent involves the incorporation of small particles of the insoluble active agent in a matrix material, as described in PCT/US2003/041703 which is incorporated herein by reference in its entirety. The matrix material is then suspended in a liquid feedstock which is spray dried to form solid particles comprising the matrix material and the particles of insoluble active agent. However, this process often involves the step of milling or otherwise reducing the size of the active agent particles. For some active agents, it is difficult to reduce the size a desired amount. In addition, for some active agents, the size reduction process may alter the active agent and decrease the stability of the active agent.
Spray drying of feedstocks comprising a hydrophobic active agent and/or co-solvents such as ethanol and water have been described, for example, in U.S. Pat. Nos. 5,976,574, 5,985,248, and 6,001,336, all of which are incorporated herein by reference in their entireties. However, the co-solvent spray drying of some poorly water-soluble active agents often results in particles having less than optimal particle characteristics. For example, due to the limited selection of suitable excipients that may be used in the formulation, particles comprising poorly water-soluble active agents that have been produced by co-solvent spray drying have shown less than desirable aerosolization characteristics.
In addition, it is also sometimes desirable to provide particles that comprise an active agent coated with a coating layer. The coating layer may be useful in improving the dispersibility of the particles. Coating layers may also be provided for masking the taste of an active agent when the active agent is being administered in an oral dosage form, as an oral dissolving tablet, or as an aerosolizable powder. Coatings may also be applied to active agents in order to provide sustained release properties to the active agent. However, it has been difficult to coat water-insoluble active agents.
Therefore, it is desirable to be able to prepare a pharmaceutical formulation comprising a water-insoluble active agent and a more water soluble excipient. It is further desirable to formulate the water-insoluble active agent in a highly dispersible, aerosolizeable, and/or coated manner. It is further desirable to formulate the water-insoluble active agent in a manner that increases the stability of the active agent.